The PDLIM5 gene and lithium prophylaxis: An association and gene expression analysis in Sardinian patients with bipolar disorder

Section of Clinical Pharmacology, Department of Neurosciences B.B. Brodie, University of Cagliari, SS 554, km. 4,500, 09042 Monserrato, Cagliari, Italy.
Pharmacological Research (Impact Factor: 4.41). 05/2008; 57(5):369-73. DOI: 10.1016/j.phrs.2008.03.011
Source: PubMed


A number of studies support the notion that lithium interacts with the protein kinase C (PKC) pathway, an important mediator of several intracellular responses to neurotransmitter signaling. PDLIM5 (PDZ and LIM domain 5; LIM) is an adaptor protein that selectively binds the isozyme PKC(epsilon) to N-type Ca(2+) channels in neurons. We tested for an association between three single nucleotide polymorphisms (SNPs) at the PDLIM5 gene and lithium prophylaxis in a Sardinian sample comprised of 155 bipolar patients treated with lithium. In order to evaluate whether PDLIM5 expression interacts with lithium response, we carried out gene expression analysis in lymphoblastoid cells of 30 bipolar patients. No association was shown between PDLIM5 polymorphisms and lithium response. When PDLIM5 expression was evaluated, no significant differences were detected between Full Responders to lithium (total score>or=7) and other patients (total score<or=6). Our negative findings do not exclude involvement of PDLIM5 in lithium prophylaxis, and further investigation is warranted.

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    • "Lithium attenuates LPA-induced calcium response in BD LCLs Perova et al., 2010; Wasserman et al., 2004 Bcl-2 gene is association with calcium signaling abnormalities in BD LCLs Machado-Vieira et al., 2011; Uemura et al., 2011 TG-induced calcium response is higher in BD LCLs Kato et al., 2003 Perova et al., 2008 Lithium attenuates TG-induced calcium response in BD LCLs Wasserman et al., 2004 Perova et al., 2010 Calcium signaling related gene LIM is downregulated in BD LCLs Iwamoto et al., 2004b Iwamoto et al., 2004a: Squassina et al., 2008 ER stress genes are upregulated in BD LCLs Hayashi et al., 2009; So et al., 2007 "
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    ABSTRACT: Background: There is an emerging interest in the use of cellular models to study psychiatric disorders. We have systematically reviewed the application of cellular models to understand the biological basis of bipolar disorder (BD). Method: Published scientific literature in MEDLINE, PsychINFO and SCOPUS databases were identified with the following search strategy: [(Lymphoblastoid OR Lymphoblast OR Fibroblast OR Pluripotent OR Olfactory epithelium OR Olfactory mucosa) AND (Bipolar disorder OR Lithium OR Valproate OR Mania)]. Studies were included if they had used cell cultures derived from BD patients. Results: There were 65 articles on lymphoblastoid cell lines, 14 articles on fibroblasts, 4 articles on olfactory neuronal epithelium (ONE) and 2 articles on neurons reprogrammed from induced pluripotent stem cell lines (IPSC). Several parameters have been studied, and the most replicated findings are abnormalities in calcium signaling, endoplasmic reticulum (ER) stress response, mitochondrial oxidative pathway, membrane ion channels, circadian system and apoptosis related genes. These, although present in basal state, seem to be accentuated in the presence of cellular stressors (e.g. oxidative stress – rote- none; ER stress – thapsigargin), and are often reversed with in-vitro lithium. Conclusion: Cellular modeling has proven useful in BD, and potential pathways, especially in cellular resilience related mechanisms have been identified. These findings show consistency with other study designs (genome-wide association, brain-imaging, and post-mortem brain expression). ONE cells and IPSC reprogrammed neurons represent the next generation of cell models in BD. Future studies should focus on family-based study designs and combine cell models with deep sequencing and genetic manipulations.
    Journal of Affective Disorders 05/2015; 184:36-50. DOI:10.1016/j.jad.2015.05.037 · 3.38 Impact Factor
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    • "Lithium interacts with the PKC pathway, a mediator of intracellular responses to neurotransmitter signalling, and PDLIM5 is an adaptor protein that selectively binds the isozyme PKC epsilon to N-type calcium channels in neurons. Squassina et al. [56] did not find an association between the PDLIM5 gene polymorphisms and lithium response. "
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    ABSTRACT: Mood stabilizers form a cornerstone in the long-term treatment of bipolar disorder. The first representative of their family was lithium, still considered a prototype drug for the prevention of manic and depressive recurrences in bipolar disorder. Along with carbamazepine and valproates, lithium belongs to the first generation of mood stabilizers, which appeared in psychiatric treatment in the 1960s. Atypical antipsychotics with mood-stabilizing properties and lamotrigine, which were introduced in the mid-1990s, form the second generation of such drugs. The response of patients with bipolar disorder to mood stabilizers has different levels of magnitude. About one-third of lithium-treated patients are excellent responders, showing total prevention of the episodes, and these patients are clinically characterized by an episodic clinical course, complete remission, a bipolar family history, low psychiatric co-morbidity and a hyperthymic temperament. It has been suggested that responders to carbamazepine or lamotrigine may differ clinically from responders to lithium. The main phenotype of the response to mood stabilizers is a degree of prevention against recurrences of manic and depressive episodes during long-term treatment. The most specific scale in this respect is the so-called Alda scale, where retrospective assessment of lithium response is scored on a 0-10 scale. The vast majority of data on genetic influences on the response to mood stabilizers has been gathered in relation to lithium. The studies on the mechanisms of action of lithium and on the neurobiology of bipolar disorder have led to the identification of a number of candidate genes. The genes studied for their association with lithium response have been those connected with neurotransmitters (serotonin, dopamine and glutamate), second messengers (phosphatidyl inositol [PI], cyclic adenosine-monophosphate [cAMP] and protein kinase C [PKC] pathways), substances involved in neuroprotection (brain-derived neurotrophic factor [BDNF] and glycogen synthase kinase 3-β [GSK-3β]) and a number of other miscellaneous genes. There are no published pharmacogenomic studies of mood stabilizers other than lithium, except for one study of the X-box binding protein 1 (XBP1) gene in relation to the efficacy of valproate. In recent years, a number of genome-wide association studies (GWAS) in bipolar disorders have been performed and some of those have also focused on lithium response. They suggest roles for the glutamatergic receptor AMPA (GRIA2) gene and the amiloride-sensitive cation channel 1 neuronal (ACCN1) gene in long-term lithium response. A promise for better elucidating the genetics of lithium response has been created by the formation of the Consortium on Lithium Genetics (ConLiGen) to establish the largest sample, to date, for the GWAS of lithium response in bipolar disorder. The sample currently comprises more than 1,200 patients, characterized by their response to lithium treatment according to the Alda scale. Preliminary results from this international study suggest a possible involvement of the sodium bicarbonate transporter (SLC4A10) gene in lithium response. It is concluded that the pharmacogenetics of response to mood stabilizers has recently become a growing field of research, especially so far as the pharmacogenetics of the response to lithium is concerned. Clearly, the ConLiGen project is a highly significant step in this research. Although the results of pharmacogenetic studies are of significant scientific value, their possible practical implications are yet to be seen.
    CNS Drugs 02/2013; 27(3). DOI:10.1007/s40263-013-0040-7 · 5.11 Impact Factor
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    • "Previous pharmacotherapy studies showed an interaction between lithium and the LIM domain in improving manic symptoms in BPD through the normalization of PKC activity [16,17]. On the other hand, one study showed no interaction between lithium prophylaxis and the LIM domain [20]. Currently, atypical antipsychotics that have mood stabilizer properties are frequently used to treat BPD because of their improved tolerability and efficacy [21]. "
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    ABSTRACT: Background One of the genes suggested to play an important role in the pathophysiology of bipolar disorder (BPD) is PDLIM5, which encodes LIM domain protein. Our main objective was to examine the effect of olanzapine treatment on PDLIM5 mRNA expression in the peripheral blood leukocytes of BPD patients. Methods We measured the expression of PDLIM5 mRNA from 16 patients with BPD Type I after 0, 4, and 8 weeks of treatment with olanzapine using quantitative real-time PCR. The Young Mania Rating Scale was used to evaluate the severity of manic symptoms in BPD patients. We also compared PDLIM5 mRNA expression in treatment-naïve BPD patients with that in healthy control subjects. Results No significant difference was found in PDLIM5 mRNA expression between patients before olanzapine treatment and following 4 and 8 weeks of treatment (p>0.05). Although we observed a significant reduction in the severity of manic symptoms in all BPD patients (p<0.05), the effectiveness of the medication did not significantly correlate with the expression of PDLIM5 mRNA (p>0.05). Interestingly, PDLIM5 mRNA expression differed significantly between treatment-naïve BPD patients and healthy control subjects (p=0.002). Conclusion PDLIM5 mRNA expression did not appear to be a reflection of the efficacy of olanzapine in reducing the manic symptoms of BPD. The significant difference in expression of PDLIM5 mRNA in the peripheral blood leukocytes of treatment-naïve BPD patients versus that of healthy control subjects, however, suggests that it may be a good biological marker for BPD.
    BMC Medical Genetics 10/2012; 13(1):91. DOI:10.1186/1471-2350-13-91 · 2.08 Impact Factor
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